1. Field of the Invention
The present invention relates to chemical conjugates for the selective delivery of anticancer drugs to tumor cells. More particularly, the invention relates to chemical conjugates for the delivery of non-toxic pro-cytotoxic drugs to target tumor cells that are metabolized by intracellular endogenous enzymes to cytotoxic drugs.
2. Description of the Background Art
It is well known in current chemotherapy protocols to administer anti-mitotic drugs such as adriamycin, vincristine, cisplatin, doxorubicin, daunomycin and methotrexate, toxins such as diphtheria toxin, pseudomonas toxin and ricin, and anti-tumor drugs such as cyclophosphamide and isophosphamide in cancer chemotherapy. Unfortunately, these drugs also have acute undesirable side effects on the normal cells of the patient, thus severely limiting the doses that can safely be administered. For a review, see DeVita, "Principles of Cancer Therapy", pages 765-788, in Petersdorf et al., Principles of Internal Medicine, 10th ed., McGraw-Hill, N.Y., 1983. In addition, many tumor cells are known to exhibit or to develop multidrug resistance, which also limits the effectiveness of cancer chemotherapy. For a review, see Kane et al, J. Bioenerget. Biomembr., 22:593 (1990).
Many approaches have been explored to improve the effectiveness and specificity of cancer chemotherapy. One approach has been to attempt to specifically direct anticancer drugs to malignant cells, so that their effect on normal cells would be minimal; this approach is generally referred to as "drug targeting." In one example of this approach, the anticancer drug is conjugated to a homing agent which is an antibody, preferably a monoclonal antibody ("mAb"), that is selected to be complementary to a tumor-associated or tumor-specific antigen. It is expected that the cytotoxic drug will be released from the conjugate at the tumor cells, and thereafter exert its toxic effects on the target cells. There are, however, several disadvantages to using antibodies as delivery agents. Internalization of antibody conjugates into cells is unpredictable. Tumor-associated antigens may be heterogeneous. The antibody itself may be antigenic and produce an undesirable immune response in the patient. The antibody might bind via its Fc receptors even to normal cells lacking the target antigen. It is difficult to attach a large number of drug molecules to an antibody without compromising the latter's complementariness. Finally, the high molecular weight of antibodies results in slow diffusion through body spaces and into solid tumor masses.
In another example of the aforementioned targeting approach, the drug is conjugated to a biodegradable polyamino acid macromolecular carrier or to such a polyamino acid carrier that is also linked to a homing agent. Theoretically, degradation of the polyamino acid carrier in the target cells releases the cytotoxic drug. Unfortunately, the use of a polyamino acid carrier encounters many of the aforementioned problems associated with the use of antibodies as drug carriers. Such bulky polyamino acid carriers may reduce the ability of the conjugate to penetrate many tumors efficiently, particularly when the conjugate also contains a protein homing agent.
It is also known to directly conjugate toxins to non-immunoglobulin homing agents, generally peptides, proteins, growth factors or hormones that react with specific cell receptors. Unfortunately, such delivery systems also generally show high and unpredictably variable toxicity for normal cells, as well as for tumor cells, in part because of a multiplicity of target cells for many of the aforementioned agents and in part because of extracellular release of the toxin.
An alternate strategy is to use a mAb as a delivery agent for an enzyme that is theoretically capable of generating within tumor masses low molecular weight cytotoxic drugs from concurrently or sequentially administered relatively noncytotoxic precursors ("prodrugs" or "procytotoxic drugs"). The drugs generated in this manner would be theoretically expected to diffuse into tumor cells and cause their growth inhibition or death (for a review, see Senter et al., Bioconjugate Chem., 4:3 (1993)). Unfortunately, plasma and other normal tissues are often capable of activating the prodrugs, due in part to the presence elsewhere of the converting enzyme and in part to the binding of antibody-enzyme conjugate at non-tumor sites, likely through Fc receptors (see, e.g., Antoniw et al., Brit. J. Cancer, 62:909 (1990)). In addition, the targeted enzymes are generally of microbial origin (U.S. Pat. No. 4,975,278), thus potentially producing antibody responses in humans.
It would be highly desirable to have available a drug delivery system that delivers a chemotherapeutic drug primarily to tumor cells, in which the drug is essentially innocuous extracellularly or even in normal cells, and in which the drug is innocuous even in tumor cells until one or more endogenous intracellular enzymes concentrated in tumor cells converts the prodrug into a cytotoxic drug. Such a drug delivery system has been discovered and is described below.